NM_014946.4(SPAST):c.1507C>T (p.Arg503Trp) AND Hereditary spastic paraplegia 4

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Apr 27, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000204046.21

Allele description

NM_014946.4(SPAST):c.1507C>T (p.Arg503Trp)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1507C>T (p.Arg503Trp)

HGVS:

NC_000002.12:g.32141917C>T
NG_008730.1:g.83307C>T
NM_001363823.2:c.1504C>T
NM_001363875.2:c.1408C>T
NM_001377959.1:c.1411C>T
NM_014946.4:c.1507C>TMANE SELECT
NM_199436.2:c.1411C>T
NP_001350752.1:p.Arg502Trp
NP_001350804.1:p.Arg470Trp
NP_001364888.1:p.Arg471Trp
NP_055761.2:p.Arg503Trp
NP_055761.2:p.Arg503Trp
NP_955468.1:p.Arg471Trp
LRG_714t1:c.1507C>T
LRG_714:g.83307C>T
LRG_714p1:p.Arg503Trp
NC_000002.11:g.32366986C>T
NM_014946.3:c.1507C>T
Q9UBP0:p.Arg503Trp

Protein change:

R470W

Links:

UniProtKB: Q9UBP0#VAR_026762; dbSNP: rs864622162

NCBI 1000 Genomes Browser:

rs864622162

Molecular consequence:

NM_001363823.2:c.1504C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1408C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1411C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1507C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1411C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hereditary spastic paraplegia 4
Synonyms:: Spastic paraplegia 4, autosomal dominant; Familial spastic paraplegia autosomal dominant 2
Identifiers:: MONDO: MONDO:0008438; MedGen: C1866855; Orphanet: 100985; OMIM: 182601

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000259516	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 31, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16055926, 17594340, 18701882, 20932283, 12552568, 26374131, 28492532
SCV000996004	Codex Genetics Limited	no assertion criteria provided	Pathogenic (Feb 28, 2019)	germline	provider interpretation	PubMed (6) [See all records that cite these PMIDs] 20932283, 17594340, 12552568, 16055926, 18701882, 26374131
SCV002579740	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 17, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003842143	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12552568, 26374131, 25741868
SCV003920821	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 27, 2023)	germline	research	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing, research, provider interpretation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia.

Alvarez V, Sánchez-Ferrero E, Beetz C, Díaz M, Alonso B, Corao AI, Gámez J, Esteban J, Gonzalo JF, Pascual-Pascual SI, López de Munain A, Moris G, Ribacoba R, Márquez C, Rosell J, Marín R, García-Barcina MJ, Del Castillo E, Benito C, Coto E; Group for the Study of the Genetics of Spastic Paraplegia..

BMC Neurol. 2010 Oct 8;10:89. doi: 10.1186/1471-2377-10-89.

PubMed [citation]

PMID:: 20932283
PMCID:: PMC2964648

See all PubMed Citations (8)

Details of each submission

From Invitae, SCV000259516.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

ClinVar contains an entry for this variant (Variation ID: 219575). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 16055926, 17594340, 18701882, 20932283). This variant is present in population databases (no rsID available, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 503 of the SPAST protein (p.Arg503Trp). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPAST protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg503 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been observed in individuals with SPAST-related conditions (PMID: 12552568, 26374131), which suggests that this may be a clinically significant amino acid residue.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Codex Genetics Limited, SCV000996004.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	PubMed (6)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002579740.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From 3billion, SCV003842143.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000219575). Different missense changes at the same codon (p.Arg503Leu, p.Arg503Pro) have been reported to be associated with SPAST related disorder (PMID: 12552568, 26374131). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), SCV003920821.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Aug 4, 2024

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